Process for the treatment of particles for use in pharmaceutical formulations

ABSTRACT

A process for the surface treatment of particles suitable for use in a pharmaceutical formulation, which comprises preparing in a temperature controlled environment a saturated solution of the substance of which the particles to be treated are composed; suspending the particles to be treated in said saturated solution; adjusting the temperature to a predetermined level in the direction of increased solubility of said substance; and harvesting the treated particles.

This invention relates to an improved process for the treatment ofparticles for use in pharmaceutical formulations, especially forinhalation formulations.

A number of drugs are available to treat patients with asthma or otherrespiratory disorders. One preferred way of administering such drugs isby inhalation, and a number of different types of inhalers, specificallymetered dose inhalers, nebulisers, and dry powder inhalers, areavailable.

The efficacy of administering drugs by inhalation depends criticallyupon the physical properties of the particles being inhaled. In general,drug particles of relatively small particle size are carried by carrierparticles of a much larger particle size. On inhalation, the smallerdrug particles are stripped off from the carrier particles and carriedinto the lungs. The carrier particles remain in the back of the throat.This mechanism tends to be rather inefficient, with only a relativelysmall proportion of the drug particles reaching the lungs.

The surface texture of the particles used in an inhalation formulationplays a crucial role in the behaviour of the particles and hence uponthe clinical effectiveness of the formulation. The shape and texture ofthe carrier particle should be such as to give sufficient adhesion forceto hold the drug particles to the surface of the carrier particlesduring manufacture of the formulation and storage in the inhaler, butsuch as to allow the dispersion of the drug particles into the lungs oninhalation.

In the case of known carriers, the surface rugosity of the dominantcrystalline face of a commercial grade carrier particle is usually roughon a micrometer scale, with an array of asperities and clefts in itssurface. The site of an asperity or a cleft is believed to be an area ofhigh surface free energy. The drug particles are preferentiallyattracted to and adhere more strongly to high energy sites causing largevariability and potentially reduced dispersibility of the drug particlesfrom the carrier surface.

Methods are known for producing perfectly smooth particles. Colombo etal, Respiratory Drug Delivery VII, 2000, 629-631, and WO 01/05429,describe a technique for smoothing the surface of lactose particles foruse in inhalation mixtures. In this method, lactose particles arephysically modified in the bowl of a high-speed mixer, with successivesteps of wetting with a solvent and drying under vacuum. Such a physicalsmoothing method is claimed to be capable of producing perfectly smoothparticles. It is not, however, susceptible to precise control and hencecannot give particles with a carefully defined surface rugosity, andwould be very time-consuming to carry out on an industrial scale.

Further, carrier particles with completely smooth surfaces present theirown difficulties. Drug particles bind too strongly to perfectly smoothsurfaces and hence they are difficult to dislodge from the carrierparticles when the formulation is inhaled.

It would therefore be highly advantageous to dramatically decrease thedegree of high surface free energy sites on conventional carrierparticles without producing a perfectly smooth particle, and to produceparticles with well-defined surface roughness on a nanometer scale.

A number of techniques are known for crystallising particles out ofsolution under conditions such that the crystals have particular surfaceproperties. For example, WO 99/48475 describes a method of preparingcrystals of particles suitable for use in inhalation which comprisescrystallising particles from a system in which the viscosity of themedium is adjusted and controlled.

U.S. Pat. No. 5,376,386 describes and claims a particulate carriersuitable for use in inhalers having an average particle size of from 5to 1000 microns and a rugosity of less than 1.75. Such particles aremade by a process of crystallisation from a saturated aqueous solutionby the addition of a water immiscible organic solvent and a solventwhich is miscible with both water and the immiscible solvent andcontrolling the conditions under which crystallisation and crystalgrowth occurs.

Such crystallisation processes have however generally proved to beunsatisfactory, as crystallisation is inherently difficult to control.Because of this, alternative approaches to the problem of optimisinginhalation formulations have been proposed. One such approach isdescribed in U.S. Pat. No. 6,153,224. Here, additive particles areattached to the surfaces of the carrier particles to promote the releaseof the drug particles from the carrier particles. Such a processsignificantly increases the cost and complexity of the formulationprocess.

The present invention has as its objective the provision of a processfor the treatment of particles suitable for use in pharmaceuticalformulations which avoids various of the disadvantages of prior artprocesses.

Accordingly the present invention provides a process for the surfacetreatment of particles suitable for use in a pharmaceutical formulation,which comprises the steps of:

-   -   i) preparing in a temperature controlled environment a saturated        solution of the substance of which the particles to be treated        are composed;    -   ii) suspending the particles to be treated in said saturated        solution;    -   iii) adjusting the temperature to a predetermined level in the        direction of increased solubility of said substance; and    -   iv) harvesting the treated particles.

The process of the present invention may be applied to any solubleparticles suitable for use in a pharmaceutical formulation, and isespecially valuable when applied to carrier particles or to drugparticles for use in inhalation formulations. Preferably the particlesto be treated are formed primarily of crystalline material. Knowntechniques for the manufacture or treatment of crystalline particlessuch as high energy milling or micronisation induce varying degrees ofdisorder to the surfaces of the processed particles of crystallinematerial. Such processes generate amorphous disorder in the nominallycrystalline material, such amorphous regions being mainly concentratedat the surface. The process of the invention will preferentially aid inthe removal of the thermodynamically unstable amorphous regions, leadingto an enhanced stability of the crystalline particles.

Carrier particles prepared by the process of the invention for use ininhaler formulations preferably have a median diameter in the range offrom 50 to 250 microns, preferably 63 to 90 microns. Preferably at least95% of the particles will be of a size which falls within these ranges.

With proper control of the process conditions, the process of theinvention may if desired be carried out such that the overall size ofthe particles used as starting material in the process of the inventionwill not differ substantially from that of the harvested particles.Therefore in a preferred embodiment of the invention the particles to betreated by the process of the invention have a mean diameter in therange of from 50 to 250 microns, preferably 63 to 90 microns.

The process of the invention may be applied to any soluble carrieruseful in inhaler compositions, for example monosaccharides such aslactose, glucose, fructose, mannitol, arabinose, xylitol and dextroseand their monohydrates, disaccharides such as trehalose, maltose orsucrose, and polysaccharides such as dextrins or dextrans. Especiallypreferred carriers include glucose, fructose, mannitol, sucrose andlactose and their monohydrates. Lactose and its monohydrate areparticularly preferred.

The process of the invention may also advantageously be applied to drugparticles for use in inhalation formulations. Such drug particles whichmay be prepared by the process of the invention preferably have a mediandiameter in the range of from 1 to 10 microns. Typical drugs includesalbutamol sulphate, terbutaline sulphate, salmeterol xinafoate,fenoterol and formeterol, and corticosteroids such as fluticasonepropionate, budesonide and beclomethasone. Another area of applicationfor the process of the invention include particles for use in solidbased suspensions for oral administration or inhalation, as well as forany powdered drug material. The process of the invention is expected toaid the maintenance of stability of drug powders during storage.

Steps (i) and (ii) of the process of the invention may be carried out asdiscrete stages, or they may be integrated into a single process step bytaking a quantity of particles in excess of that required to beharvested in step (iv) of the process and adding these particles to asuitable solvent in such an amount that a certain proportion thereofwill dissolve to form the saturated solution and the remaining particleswill remain to be treated by step (iii) of the process.

The solvent used in the process of the invention will of course bechosen depending upon the identity of the particles to be treated.Preferably the particles to be treated are composed of a water solublematerial and the solvent used in the process of the invention is water,optionally together with a co-solvent. Other solvents or solventmixtures may however be used, for example alcohols or water/alcoholmixtures or any other suitable organic solvent.

In most cases, solubility increases with temperature, and therefore step(iii) of the process of the invention will be carried out by raising thetemperature. As the temperature increases, the solution becomes able todissolve more of the solid. The process may be regarded as a surfaceetching process in which asperities on the surface of the articles to betreated are selectively etched away as the temperature increases.Etching tends to take place preferentially at those sites having highsurface free energy. Excessive etching and hence significant erosion ofmass of the particles to be treated is avoided by careful temperaturecontrol. In some cases, the solubility of the solid material willdecrease with temperature, and in this case step (iii) of the process ofthe invention will be carried out by lowering the temperature. Dependingupon the various process parameters adopted including the temperaturedifference required, the temperature may be adjusted in stepwise fashionor in a single step.

Careful control of the various process parameters enables particles witha precisely defined surface rugosity to be obtained. The time taken tocarry out the process of the invention will depend upon the resultsdesired and upon the detailed design of the apparatus used. In general,the longer the processing time during which the crystals to be treatedare in contact with the treating solution, the lower will be the surfacerugosity of the crystals harvested at the end of the process. Stirringis preferably continually applied to the solution containing theparticles being treated throughout the treatment process to maintain astable situation in which the solution does not become supersaturated.

Preferably, the particles obtained by the process of the resentinvention have a surface rugosity of between 1.05 and 1.80.

The process according to the invention may be carried out as a batchprocess or as a semi-continuous process. The equipment needed is simpleand cheap and can readily be constructed as an add-on to existingequipment for the preparation of particles for use in pharmaceuticalformulations, or for the preparation of pharmaceutical formulations.

With a knowledge of the temperature dependency of the solubility of thesubstance to be treated, it is possible by careful control oftemperature in the process according to the invention to achieve theprecise degree of etching of the particles required. The followingexpression (%σ) gives the percentage difference between the soluteconcentration at temperature T and the solute concentration at thesaturation temperature:−%σ=100×(C _(T) −C _(S))/C _(S)where C_(T) is solubility at the etching temperature and C_(S) is thesolubility at the saturation temperature. It is also possible to definean equation which describes the solubility versus temperature profile;for α-lactose monohydrate the equation is:S _(T)=19.892−0.2937T+0.0138T ²+0.00003T ³where S_(T) is the solubility of lactose in mg/100 ml water and T is thetemperature of the solution in ° C.

Thus, if the saturation temperature, etching temperature, volume of theliquid phase and the amount of material added to the system is known thewhole etching process of any particle surface can be accuratelydetermined and controlled. The process of the present invention avoidsthe difficulties inherent in crystallisation techniques. Such techniquesare inherently difficult to control and their results are difficult topredict, as every student who has tried to induce crystallisation in atest-tube will testify. Unlike crystallisation, the kinetics ofdissolution are rapid. Furthermore, once saturation conditions withinthe treatment solution are re-established following a temperaturechange, further dissolution and crystallisation are inhibited. Thismeans that the surface etching process of the present invention isextremely easy to control and predictable and consistent results canreadily be achieved between batches.

The particles prepared by the process of the invention may be harvestedby any suitable method, typically filtration. They may then be washedwith a non-solvent, sieved, and dried, ready for further processing ifrequired to prepare a pharmaceutical formulation.

The present invention avoids the problems associated with the productionof crystals by crystallisation from a solution and, because it may useas starting material any commercial-grade particles, for examplecommercial grade lactose, it is very economical in use. It may bereadily applied on an industrial scale, and adds only a small number ofadditional steps to current industrial processes for the production ofparticles for pharmaceutical formulations, especially inhalationformulations. For these reasons it is more cost effective than otherproposals to improve the preparation of such formulations.

The process of the invention is especially useful for the preparation ofparticles for use in inhaler formulations. Such particles may be carrierparticles or drug particles of both. Thus in a further aspect, thepresent invention provides a process for the preparation of an inhalerformulation comprising drug particles and carrier particles, whichcomprises the steps of treating carrier particles by process steps i) toiv) as defined above; washing and drying the thus treated carrierparticles; and blending said carrier particles with said drug particles.

In yet a further aspect, the present invention provides a process forthe preparation of an inhaler formulation comprising drug particles andcarrier particles, which comprises the steps of treating drug particlesby process steps i) to iv) as defined above; washing and drying the thustreated drug particles; and blending said drug particles with saidcarrier particles.

In both these aspects, an especially preferred embodiment is when thecarrier particles comprise lactose and the drug particles comprisesalbutamol.

The following Examples illustrate the invention. In the Figures, thewhite bars indicate the scale, the length of the bar being equivalent to10 μm.

EXAMPLE 1

Inhalation grade α-lactose (Lactochem (Trade mark), available fromBorculo Whey) was sieve fractioned in the particle size range 63-90microns. A saturated solution of α-lactose monohydrate in water wasprepared and continually stirred at a constant temperature of 25° C.Temperature within the vessel was controlled to within 0.1° C. via arefrigerated controlled water bath. 100 ml of the saturated solution wassubsequently filtered into a dissolution vessel, which was maintained atthe saturation temperature, and 50 g of sieved (63-90 microns) α-lactosemonohydrate was added to the saturated solution in the dissolutionvessel.

The temperature within the dissolution vessel was increased by 5° C. andthe mixture was stirred for a period of 30 minutes. The mixture was thenfiltered, washed with cyclohexane, sieved to retrieve particles in thesize range 63 to 90 microns, and dried.

Representative scanning electron microscopy (SEM) topographical imagesof the resulting lactose particles are shown in FIG. 1.

EXAMPLES 2 TO 5

The method of Example 1 was repeated except that the temperature withinthe dissolution vessel was raised by differing amounts. RepresentativeSEM images of the resulting lactose particles are shown in FIGS. 2 to 5.

For comparison, representative SEM images of the untreated α-lactosemonohydrate used as starting material in Examples 1 to 5 are shown inFIG. 6. A clear reduction in surface rugosity of the particles treatedin accordance with Example 1 to 5 compared with the untreated particlescan be seen.

EXAMPLE 6 In Vitro Testing of Salbutamol Availability

Physical blends of micronised salbutamol sulphate and particles ofα-lactose monohydrate (untreated and treated in accordance with Examples1 to 5) in a ratio of 1:67.5 w/w were prepared by mixing in a turbulamixer for 30 minutes. These mixtures were then loaded into gelatincapsules for a monohaler device for in vitro measurements. Each capsulecontained a 400 microgram dose of salbutamol sulphate. In vitro aerosoldeposition was performed using a twin stage impinger by the standardmethod described in European Pharmacopaeia 1997 at 60 L/min. This methodmodels the aerosolisation behaviour of a dry powder inhaler formulation.The fine particle fraction is calculated as the percentage of the totalamount of drug emitted from the device that reaches the lower stage(stage 2) of the twin stage impinger (the particle “cut-off” diameterfor the device at 60 L/min is dae less than 6.4 micron—i.e. particles ofgreater than this diameter are not permitted to pass to the lowerstage). The fine particle fraction provides an indication of theproportion of the drug particles which would reach the deep lung in apatient, and is hence a measure of the pharmaceutical efficacy of aninhalation formulation. Measurements were performed in replicates ofthree. Drug analysis was performed by fluorescence spectroscopy.

The results for the untreated and treated lactose surfaces are shown inthe following Table. The data in the Table shows the average salbutamolsulphate content in micrograms recovered from each stage of the twinstage impinger, and the fine particle fraction calculated from thismeasurement.

The results show that use of lactose particles treated by the process ofthe present invention results in an increase in the deposition ofsalbutamol particles in the lower stage of the twin stage impinger,which indicates a significantly improved availability of the drug invivo. TABLE Weight of particles (less than 6.4 μm) reaching stages 1 and2 of the twin stage Example Etching impinger Fine particle No.Conditions Stage 1 Stage 2 fraction (%) 1  5° C. etch 137.7 79.35 25.3(FIG. 1) 2 10° C. etch 202.5 86.4 19.7 (FIG. 2) 3 15° C. etch 159.4123.6 33.3 (FIG. 3) 4 20° C. etch 161.4 93.3 24.8 (FIG. 4) 5 25° C. etch201.0 100.0 23.5 (FIG. 5) Comparison Untreated 199.5 47.4 13.9 (FIG. 6)particles

1. A process for the surface treatment of particles suitable for use ina pharmaceutical formulation, comprising the steps of: i) preparing in atemperature controlled environment a saturated solution of the substanceof which the particles to be treated are composed; ii) suspending theparticles to be treated in said saturated solution; iii) adjusting thetemperature to a predetermined level in the direction of increasedsolubility of said substance; and iv) harvesting the treated particles.2. The process according to claim 1, wherein the particles to be treatedare carrier particles or drug particles for use in inhalationformulations.
 3. The process according to claim 1, in which theparticles to be treated are carrier particles having a median diameterin the range of from 63 to 90 microns.
 4. The process according to claim1 in which the particles to be treated are lactose or its monohydrate.5. The process according to claim 1, in which the particles to betreated are drug particles having a median diameter in the range of from1 to 10 microns.
 6. The process according to claim 1, in which theparticles to be treated are composed of a water soluble material and thesolvent used in the process of the invention comprises water.
 7. Theprocess according to claim 1, in which the particles produced by theprocess have a surface rugosity of between 1.05 and 1.80.
 8. A processfor the preparation of an inhaler formulation comprising drug particlesand carrier particles, the process comprising the steps of: i) preparingin a temperature controlled environment a saturated solution of thesubstance of which the particles to be treated are composed; ii)suspending the particles to be treated in said saturated solution; iii)adjusting the temperature to a predetermined level in the direction ofincreased solubility of said substance; and iv) harvesting the treatedparticles; v) washing and drying the thus treated carrier particles; andvi) blending said carrier particles with drug particles.
 9. A processfor the preparation of an inhaler formulation comprising drug particlesand carrier particles, the process comprising the steps of: i) preparingin a temperature controlled environment a saturated solution of thesubstance of which the particles to be treated are composed; ii)suspending the particles to be treated in said saturated solution; iii)adjusting the temperature to a predetermined level in the direction ofincreased solubility of said substance; and iv) harvesting the treatedparticles; v) washing and drying the thus treated drug particles; andvi) blending said drug particles with carrier particles.
 10. The processas claimed in claim 8, in which the carrier particles comprise lactoseor its monohydrate and the drug particles comprise salbutamol.
 11. Aprocess as claimed in claim 9, in which the carrier particles compriselactose or its monohydrate and the drug particles comprise salbutamol.